3′-prodrugs of 2′-deoxy-β-L-nucleosides
View Patent ↗The present invention relates to compounds, compositions and methods for the treatment of a host infected with a hepatitis B virus. Specifically, compound and compositions of 3′-esters of 2′-deoxy-β-L-nucleosides are disclosed, which can be administered either alone or in combination with other anti-hepatitis B agents. Compound and compositions of 3′,5′-diesters of 2′-deoxy-β-L-nucleosides are disclosed, which can be administered either alone or in combination with other anti-hepatitis B agents, are also disclosed.
1. A compound of the formula
or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising a compound of the formula
or a pharmaceutically acceptable salt thereof, in combination with β-L-deoxyribothymidine.
3. A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein
R 2 is an amino acid residue; and
R 3 and R 4 are independently H, straight chained, branched or cyclic alkyl, dialkylaminoalkylene, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate prodrug.
4. The compound of claim 3 , wherein R 2 is an amino acid residue of the formula C(O)C(R 8 )(R 9 )(NR 10 R 11 ), wherein
R 8 is the side chain of an amino acid and wherein R 8 can optionally be attached to R 10 to form a ring structure; or alternatively, R 8 is an alkyl, aryl, heteroaryl or heterocycle;
R 9 is hydrogen, alkyl or aryl; and
R 10 and R 11 are independently hydrogen, acyl or alkyl.
5. The compound of claim 4 , wherein R 2 is L-valinyl.
6. The compound of claim 3 , wherein R 3 and R 4 are hydrogen.
7. The compound of claim 3 , wherein R 3 is hydrogen and R 4 is dimethylaminomethylene.
8. The compound of claim 3 , wherein R 3 is hydrogen and R 4 is CO-alkyl.
9. The compound of claim 3 , wherein R 3 is hydrogen and R 4 is CO-methyl.
10. The compound of claim 3 , wherein R 3 is hydrogen and R 4 is L-valinyl.
11. A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein
R 2 is an amino acid residue.
12. The compound of claim 11 , wherein R 2 is an amino acid residue of the formula C(O)C(R 8 )(R 9 )(NR 10 R 11 ), wherein
R 8 the side chain of an amino acid and wherein R 8 can optionally be attached to R 10 to form a ring structure; or alternatively, R 8 an alkyl, aryl, heteroaryl or heterocycle;
R 9 is hydrogen, alkyl or aryl; and
R 10 and R 11 are independently hydrogen, acyl or alkyl.
13. The compound of claim 12 , wherein R 2 is L-valinyl.
14. A pharmaceutical composition comprising an effective anti-HBV amount of a compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein
R 2 is an amino acid residue; and
R 3 and R 4 are independently H, straight chained, branched or cyclic alkyl, dialkylaminoalkylene (in particular, dimethylaminomethylene), CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate prodrug; with a pharmaceutically acceptable carrier or diluent.
15. The pharmaceutical composition of claim 14 , wherein R 2 is an amino acid residue of the formula C(O)C(R 8 )(R 9 )(NR 10 R 11 ), wherein
R 8 is the side chain of an amino acid and wherein R 8 can optionally be attached to R 10 to form a ring structure; or alternatively, R 8 is an alkyl, aryl, heteroaryl or heterocycle;
R 9 is hydrogen, alkyl or aryl; and
R 10 and R 11 are independently hydrogen, acyl or alkyl.
16. The pharmaceutical composition of claim 15 , wherein R 2 is L-valinyl.
17. The pharmaceutical composition of claim 14 , wherein R 3 and R 4 are hydrogen.
18. The pharmaceutical composition of claim 14 , wherein R 3 is hydrogen and R 4 is dimethylaminomethylene.
19. The pharmaceutical composition of claim 14 , wherein R 3 is hydrogen and R 4 CO-alkyl.
20. The pharmaceutical composition of claim 14 , wherein R 3 is hydrogen and R 4 is CO-methyl.
21. The pharmaceutical composition of claim 14 , wherein R 3 is hydrogen and R 4 is L-valinyl.
22. A pharmaceutical composition comprising an effective anti-HBV amount of a compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein
R 2 is an amino acid residue;
with a pharmaceutically acceptable carrier or diluent.
23. The pharmaceutical composition of claim 22 , wherein R 2 is an amino acid residue of the formula C(O)C(R 8 )(R 9 )(NR 10 R 11 ), wherein
R 8 is the side chain of an amino acid and wherein R 8 can optionally be attached to R 10 to form a ring structure; or alternatively, R 8 is an alkyl, aryl, heteroaryl or heterocycle;
R 9 is hydrogen, alkyl or aryl; and
R 10 R 11 are independently hydrogen, acyl or alkyl.
24. The pharmaceutical composition of claim 23 , wherein R 2 is L-valinyl.
25. A pharmaceutical composition comprising a compound of the formula
or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier or diluent.